Undetectable or subtherapeutic serum levels of antipsychotic drugs preceding switch to clozapine

Lennart Kyllesø,Øystein Karlstad,Ole A Andreassen,Espen Molden,Robert Løvsletten Smith

doi:10.1038/s41537-020-0107-7

Abstract

Adequate antipsychotic treatment intensity is required for defining treatment-resistant schizophrenia (TRS) and justifying clozapine treatment. We investigated the occurrence of undetectable or subtherapeutic serum levels of oral antipsychotics preceding switch to clozapine as an endpoint of TRS. For patients starting clozapine, 12-month retrospective reviews of antipsychotic serum concentration measurements were performed in a Norwegian therapeutic drug monitoring (TDM) database from 2005 to 2017. Undetectable levels in high-sensitive analytical assays defined ‘no drug use’, while levels <50% of the lower reference range defined ‘subtherapeutic use’. Similar data were collected for patients switching to long-acting injectable (LAI) antipsychotics, as a reference of ‘no or subtherapeutic drug use’. Nineteen of 353 patients initiating clozapine (5.4%) had a recent history of undetectable antipsychotic drug levels compared to 91 of 1048 (8.7%) initiating LAI. Another 19 patients starting clozapine (5.4%) had recent events of subtherapeutic levels. In conclusion, the present retrospective study may indicate that every 10th patient starting clozapine has a recent history of undetectable or subtherapeutic serum levels of oral antipsychotics. The clinical implications of the present study for the assessment of TRS should be investigated prospectively in further studies.

Highlights

Schizophrenia is regarded as the most severe mental illness, both in terms of patient suffering and societal costs[1,2,3]
There were no significant differences in demographic characteristics between patients with and without a recent history of undetectable or subtherapeutic serum levels prior to starting clozapine (p > 0.5, Table 1), but the observed proportion of inpatients was higher in the subgroup with undetectable or subtherapeutic compared to patients with serum concentrations in the target range, i.e. 84.2% versus 69.5%, respectively (p = 0.06, Table 1)
The present descriptive study may indicate that every 10th patient starting clozapine has a recent history of undetectable or subtherapeutic serum levels of oral non-clozapine antipsychotics

Summary

Introduction

Schizophrenia is regarded as the most severe mental illness, both in terms of patient suffering and societal costs[1,2,3]. Chronic use of antipsychotic medication is regarded as necessary in the treatment of schizophrenia[4], but about onethird of the patients respond insufficiently to antipsychotics[5,6]. These patients are classified as ‘treatment resistant’ or ‘treatment refractory’. The term ‘treatment-resistant schizophrenia’ (TRS) is defined as a ‘lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration’[7,8,9]. For a better understanding of the underlying causes of TRS and for optimizing treatment in these patients, it is crucial to discriminate pseudo-resistance (inadequate treatment intensity) from a true TRS (ineffective treatment)[10]

Methods

Results

Conclusion